Recent advances in the transformation reactions of the Betti base derivatives

Betti bases are the products resulting from the one-pot multicomponent reaction involving 1-naphthol/2-naphthol, aliphatic/aromatic aldehydes, and secondary amines. This chemical process is commonly referred to as the Betti reaction. The significance of Betti bases in medicinal chemistry has grown substantially due to their diverse array of pharmacological applications. Furthermore, their synthetic utility is considerable, given their use as catalysts and ligands in asymmetric synthesis. Moreover, Mannich products, incorporating diverse functional groups such as –OH and –NH, find application in a range of organic reactions. This utilization enables the synthesis of novel C–C bond linkages and diverse heterocycles, including biologically active naphthoxazines, which hold biological applications such as antibacterial, antifungal and anticancer. The focus of this review article is on the application of aminonaphthol derivatives in transformation reactions and the synthesis of organic compounds, with particular emphasis on heterocycles.


Introduction
2][3][4] The Betti procedure can be understood as an expansion of the Mannich condensation.In this process, formaldehyde is substituted with an aromatic aldehyde, the secondary amine is replaced by ammonia, and the C-H acid is substituted with an electron-rich aromatic compound, such as 2-naphthol.This modication in reactants results in a distinct chemical transformation, broadening the scope of the traditional Mannich condensation and yielding unique products through the Betti procedure.As a result of the potential utility of

Abolfazl Olyaei
Associate professor Dr Abolfazl Olyaei was born in Tabriz, Iran in 1975.He received the BSc degree in pure chemistry from Tabriz University, Tabriz, Iran in 1999 and the MSc degree in organic chemistry from Tehran University, Tehran, Iran under the supervision of professor Mohammad Raouf Darvich in 2001.He obtained PhD degree in organic chemistry from Tehran University, Tehran, Iran under the supervision of professor Mehdi Ghandi, in 2007.He is as an associate professor in Imam Khomeini International University, Qazvin, Iran.His research interests include organic synthesis, synthesis of heterocyclic compounds, multi-component reactions, green chemistry, catalysis and organocatalysis and applications of materials and organomaterials in different sciences.

Mahdieh Sadeghpour
Associate professor Dr Mahdieh Sadeghpour was born in Qazvin, Iran in 1978.She received the BSc degree in pure chemistry from Alzahra University, Tehran, Iran in 2001 and the MSc degree in organic chemistry from Tehran University, Tehran, Iran under the supervision of assistance professor Nikoo Sedighi in 2004.She obtained PhD degree in organic chemistry from Kharazmi University, Tehran, Iran under the supervision of professor Abbas Shokravi and associate professor Abolfazl Olyaei,  in 2009.She is as an associate professor in Islamic Azad University of Qazvin, Iran.Her research eld is on the synthesis of organic compounds, multi-component reactions, synthetic methodology, green chemistry and applications of materials and nanomaterials in different sciences.
Mannich-type phenolic bases, the aminoalkylation of naphthol derivatives is a subject of current chemical interest.In recent years, numerous methodologies have reported for synthesizing these aminobenzylnaphthols, also known as Betti bases, and their bis-Betti base derivatives.These methods involve the utilization of diverse substrates such as various types of naphthols, aromatic amines, heteroaromatic amines, aliphatic and cyclic amines, instead of ammonia or diamines.Additionally, aliphatic and aromatic aldehydes or dialdehyde compounds have been employed under various conditions in recent research efforts.The typical process for the formation of the Betti bases begins with the generation of an ortho-quinone methide (o-QM) through the reaction between naphthol and aldehyde.Subsequently, the o-QM undergoes a Michael addition with an amine, resulting in the formation of the Betti base.These compounds exhibit a wide range of applications, including: enantioselective addition of diethylzinc to aldehydes, 5 crystallization-induced diastereoisomer transformation, 6 asymmetric hydrogenation and allylic substitution, 7 optoelectronic applications (uorescent chemosensors, 8 uorescence detection of Hg 2+ and Cr 3+ ions 9 and electrochemical activity 10 ) and biological properties such as anticancer agents 11 (A), antioxidant 12 (B), anti-bacterial 13 (C), antitubercular agents 14 (D), pesticidal agents 15 (E), anti-Alzheimer agents 16 (F), topoisomerase I inhibitors 17  important heterocycles such as biologically active 1,3-oxazine and naphthoxazine derivatives.Because of their broad signicance in the medicinal and pharmaceutical industries, research on the synthesis of Betti bases has been ongoing since the early twentieth century.Up to now, a limited number of reviews have been published covering the synthesis of Betti base derivatives and their applications.Indeed, there has been limited discussion on the transformation of these compounds into various organic compounds.0][21][22][23][24] In this review, we aim to offer a comprehensive overview of a wide range of methodologies pertaining to the transformation of Betti base derivatives in the synthesis of various organic compounds.Our review examines the diverse strategies employed in these transformations and explores the applications of the resulting organic compounds.

Synthesis of naphthoxazines
In 1999, Naso and co-workers reported the reaction of Betti base (S)-(+)-1 with n-butanal in EtOH at room temperature for 24 h to produce naphthoxazine (−)-2 in 68% yield.It was reduced to l-(a-N-butylaminobenzyl)-2-naphthol (S)(+)-3 in 60% yield with NaBH 4 in CH 3 OH at room temperature for 6 h (Scheme 1). 25 Aer that, Palmieri et al. described synthesis of naphthoxazine 4 by the reaction of enantiopure aminonaphthol 5 with formaldehyde in THF/H 2 O at room temperature for 15 h. 26Also, methylation of (R,R)-5 with formaldehyde in the presence of triuoroacetic acid in THF at room temperature for 4 h afforded naphthoxazine derivative (R,R)-4 in 90% yield as depicted in Scheme 2. 27 Aer that, condensation of Betti base analogue amino naphthols 6 with substituted benzaldehydes in absolute MeOH at ambient temperature for 24 h led to the formation of 1,3diaryl-2,3-dihydro-1H-naphth [1,2- 24b with paraformaldehyde in toluene at room temperature for 10-12 h.The compound 23 was also reduced with LiAlH 4 in THF at room temperature for 4-6 h affording aminonaphthol derivatives 25a and 25b in 96-98% yields (Scheme 9).The aminonaphthols 24 were found to catalyze the enantioselective ethylation of aryl aldehydes to 1-aryl-1-propanols (up to 92% ee). 34In 2009, synthesis of 1,3-oxazine derivatives 26 reported in 85-96% yields by the reaction of Betti base 27 with aromatic/ heteroaromatic aldehydes under microwave irradiation (360 W) for 10-15 min or solvent-free conditions at 60 °C for 25-40 min.The simplicity of the reaction conditions, their efficiency, and the excellent results in shorter reaction times using both method A and method B under solvent and catalyst-free conditions, constitute an attractive contribution among the existing methodologies (Scheme 10). 35er that, the condensation of Betti base 1 and aliphatic aldehydes such as 1-butanal and (MeO) 2 CHCHO in MeOH at room temperature for 30-60 minutes afforded the corresponding N,O-acetal 28 and 29 in almost quantitative yields even without the use of an acidic catalyst.Also, alkylation of 29 by RMgBr was accomplished quickly in THF at room temperature within 30 minutes to give the desired product 30 in 85-96% isolated yield.Then, the diaryl benzylamine 30 was N-debenzylated quantitatively under mild Pd/C catalytic hydrogenolysis conditions in ClCH 2 CHCl 2 /MeOH at room temperature for 2-6 h, afforded 1-substituted 2,2-dimethoxyethylamine hydrochlorides 31 in 90-99% yields.The method reported is extremely convenient and highly efficient with wide substrate scopes (Scheme 11). 36ext, the reaction of aminomethylnaphthols 32a and 32b and 33a and 33b with paraformaldehyde using Et 3 N in CHCl 3 for 6 h, phosgene in toluene/H 2 O in the presence of Na 2 CO 3 for 10 min and 4-chlorophenyl isothiocyanate in the presence of Et 3 N for 6 h followed by the reaction with MeI in MeOH using KOH at room temperature for 4 h led to naphthoxazine derivatives 34, 35, 38, 39 and 41 as shown in Scheme 12. 37 In 2010, Shi and co-workers described synthesis a series of naphtho [1,2- Aer that, a series of 8-bromo-1,3-bis(aryl)-2,3-dihydro-1Hnaphtho[1,2-e][1,3]oxazines 47 synthesized in 52-69% yields by the reaction of Betti base 48 with substituted aryl and heteroarylaldehydes in MeOH at ambient temperature for 48 h (Scheme 14).Some of the compounds found to exhibit good activity against tested bacterial and fungal strains.Compounds having uoro, chloro and methyl substituted phenyl group attached to naphthoxazine showed promising activity. 39n addition, the reaction of aminonaphthol derivatives 49 with formaldehyde in THF at room temperature for 15 h gave naphthoxazine derivatives 50 in 90-95% yields, which were reduced with sodium boronhydride in THF/HOAc at room temperature to afford the target chiral aminonaphthol ligands 51 in 78-87% yields (Scheme 15).The results of asymmetric phenyl transfer to aromatic aldehydes catalyzed by these chiral ligands 51 indicated that enantioselectivities were greatly inuenced by the electronic and steric effects of the ligands. 40n 2013, Dimitrov and co-workers have demonstrated Betti base derivatives 52 were easily transformed into the corresponding 1,3-oxazines 53a-e in 24-99% yields by reacting them with formaldehyde (in the form of paraformaldehyde or formalin) in EtOH at 20 °C or 55 °C for 30 min to 24 h (Scheme 16). 41n 2014, Khosropour and his group described stereoselective synthesis of trans-3-(5-methylisoxazol-3-yl)-3,4-dihydro-2Hnaphtho[2,3-e][1,3]oxazine derivatives 54 in high yields (75-98%) by the reaction of 1-(aryl (5-methyl-isoxazol-3-ylamino) methyl)naphthalen-2-ols 55 with aromatic aldehydes using p-TSA as catalyst under solvent-free conditions at 100 °C for 30-40 min.This reaction includes some important aspects like straightforward operation, easy workup procedure and absence of transition metal catalysts.In the proposed mechanism, rst, the Betti base attacks aryl aldehyde in the presence of the catalyst to generate the corresponding imine as the pivotal intermediate.Finally, the intermediate undergoes 6-endo-dig to give the corresponding [1,3]oxazine 54 as illustrated in Scheme 17. 42 Next, Srimannarayana et al. reported preparation of (S)naphthoxazines 56 with diastereoisomeric ratios (dr) in almost equal in 69-89% yields by the treatment of L-(+)-tartaric acid salt of the (S)-enantiomer 1 with various racemic a-alkyl dihydrocinnamic aldehydes (2-alkyl-3-phenylpropanals) 57 in MeOH at 60 °C for 25 h (Scheme 18). 43urther, a number of chiral racemic and enanthiopure thiophosphorylated thioureas 58 synthesized by the reaction of 1-(a-aminobenzyl)-2-naphthol 1 with O,O-diethyl thiophosphoryl isothiocyanate 59 in dry benzene at room temperature for 24 h.It was found that such thioureas undergo the cyclization reaction under basic conditions with hydrogen sulde elimination via two methods (method A: in dry acetone, triethylamine or 4-(dimethylamino)pyridine at room temperature for 7 days; method B: in chloroform and hexane, N,N 0 -dicyclohexylcarbodiimide at reux for 4 h) and afforded thiophosphorylated oxasines 60 as depicted in Scheme 19. 44n 2017, Paolucci and co-workers accomplished synthesis of naphthoxazines 61 in 75-94% yields by the reaction of a-epimerizable 4-hydroxybutyraldeydes 62 with (S)-Betti base 1 in MeOH at room temperature for 2 h or 2.5-20% AcOH in MeOH at 60 °C for 16-69 h.The diastereoisomeric naphthoxazines 61 underwent hydrolysis by using pre-washed resin 20 in a mixture of aq.H 2 SO 4 , THF and acetic acid within 3-5 hours, and the aldehydes are obtained with higher enantiomeric enrichment (Scheme 20). 45n 2018, Alfonsov et al. developed a method to synthesize oxazines 63 in 69-76% yields by the reaction of the racemic Betti base 1 with 2-, 3-, and 4-pyridinecarbaldehydes in benzene under reux for 4 h.In the solution, a three-component ringchain equilibrium is established between the imine form and cis-and trans-oxazines.It should be noted that the content of the imine form (CDCl 3 ) in a series of compounds 63 is signicantly lower compared with 1,3-diphenylnaphthoxazine. Trans form is predominant in all cases (Scheme 21).It can be assumed that the imine/oxazine ratio is mainly inuenced by electronic interactions, while the cis-/trans-1,3-oxazine ratio is more inuenced by steric factors. 46n 2020, a series of naphtho remarkable activities against MCF-7 (breast) and HCT116 (colon) cancers with comparable IC 50 (the half maximal inhibitory concentration) values as that of known drugs such as 5-uorouracil (5-FU).In vitro antimicrobial activities of all compounds were also evaluated against ve human pathogenic fungi strains and two bacteria (one Gram positive and one Gram yields.The oxidation of compound 69a with PhI(OAc) 2 in MeOH for 2 h afforded bisoxazinic compound 71 in 68% yield as shown in Scheme 24.Two Cu complexes and one Sc complex were prepared from compound 71.The metal complexes were employed in some reactions to test their ability to promote the transformation and the asymmetric induction. 49

Synthesis of naphthopyrrolooxazines, naphthopyridooxazines and naphthooxazinoazepines
In 2002, Hu et al. synthesized unsubstituted piperido[2,1-b] oxazine derivative 72a in 61% yield by the reaction of (S)-1 with 1,5-pentanedial in the presence of NaBH 3 CN in a buffer solution (aqueous EtOH solution of Na 2 HPO 4 -KH 2 PO 4 ) at 0 °C for 1.5 h.Similarly, 72b (59%) and 72c (51%) were obtained smoothly by using 1,4-butanedial and 1,6-hexanedial, respectively.When compounds 72 were treated with LiAlH 4 , the CO bond was cleaved selectively to yield the desired cycloaminephenols without any loss of enantiomeric excess at −10 °C in 1.5 h.The asymmetric addition of ZnEt 2 to benzaldehyde was tested in toluene with 10 mol% of cycloamine-phenol ligands to give the products in 93-96% yields and 73-99% ee (Scheme 25). 50er that, unsubstituted tetrahydropyrido-[2,1-b]oxazine 72d was obtained in 76% yield via the reaction of (S)-1 with pentane-1,5-dial in the presence of NaBH 3 CN in an aqueous buffer solution (Na 2 HPO 4 -KH 2 PO 4 ) at room temperature for 12 days.Also, the salt of (S)-1 with L-(+)-tartaric acid, which is a precursor of (S)-1 in its optical resolution, was used directly as the starting material and 72d was obtained in 61% yield within 30 min in 50% aqueous EtOH.Similarly, 72e (59%) and 72f (51%) were prepared respectively by the replacement of pentane-1,5-dial with butane-1,4-dial and hexane-1,6-dial under the same conditions.These compounds converted to non-racemic 1-[-(1azacycloalkyl)benzyl]-2-naphthols 72g-i by the selective The ligands with pyrrolidine and piperidine lead to highly efficient asymmetric induction in the addition of diethylzinc to aryl aldehydes with up to 96% yield and 99% ee (Scheme 26). 51n 2004, following Katritzky's procedure, a mixture of S-1 [as a salt of L-(+)-tartaric acid], pentane-1,5-dial and BtH in CH 2 Cl 2 was stirred at 0 °C for 5 hours.As expected, the diastereopure abenzotriazolyl-piperido[2,1-b][1,3]-oxazine 73a was obtained in 91% yield (Scheme 2).Similarly, replacement of pentane-1,5dial by butane-1,4-dial and hexane-1,6-dial, the veand seven membered azacyclic analogues 73b and 73c were obtained respectively in high yields (93% and 91%) and diastereoselectivities.Moreover, both C-Bt and C-O bonds in the oxazines 73 were cut clearly via LiAlH 4 within half hour at 0 °C to afford chiral Betti bases in high yields, which have been proved to be excellent chiral ligands in the asymmetric addition of ZnEt 2 to aldehydes (Scheme 27). 52n 2005, total syntheses of enantiopure alkaloidal natural products (2S,6R)-dihydropinidine (74a, as hydrochloride) and (2S,6R)-isosolenopsins (74b-e, as hydrochlorides) achieved with the shortest steps and unprecedented high total yields by using a strategy of the formation-cleavage of 1,3-oxazinane.First, Betti base (S)-1 [as a salt of L-(+)-tartaric acid] condensed with pentane-1,5-dial and benzotriazole to diastereopurely yield 75 in 92% yield.By using THF as solvent, a solvent controlled monoalkylation of 75 was achieved to give diastereopure 76 in 96% yield.Then 76 was alkylated with the corresponding Grignard reagent followed by N-debenzylation straightforward to amine hydrochloride by Pd/C-catalyzed hydrogenolysis in the presence of CH 2 Cl 2 to yield target products 74a-e in 90-93% yields (two steps), respectively (Scheme 28). 53n 2014, Jana and co-workers reported diastereoselective a-C-H functionalization of aliphatic N-heterocycles for the synthesis of ring fused oxazines 77.The propensity of 84 for reductive elimination of iodobenzene will generate the requisite iminium ion 85 which will be intramolecularly trapped by phenoxide anion to form trans-1,3-naphthoxazine 82. 55eb and co-workers developed an iodine-tert-butylhydroperoxide for the synthesis of 1,3-oxazines 86 in 85-94% yields from Betti bases 87 under heating at 130 °C in DMF as solvent within 15-30 min.The method uses inexpensive and nonhazardous I 2 catalyst and TBHP as the oxidant.Moreover, the reaction could easily be scaled up to multigram scale with excellent yield, in which the product can be successfully isolated by recrystallization.The proposed a tentative mechanism for the reaction is outlined in Scheme 31.First, 87 is converted to OH group of 97 followed by cyclization with the elimination of a molecule of hydrogen peroxide. 57 58er that, a functional group, the hydroxy group, was inserted into a Betti base 1 by reaction with salicylaldehyde, and the naphthoxazine derivatives thus obtained were converted by ring-closure reactions with formaldehyde, acetaldehyde, propionaldehyde or phosgene to the corresponding naphth  [1,3]benzoxazine derivative 112 in 72% yield.Further, by NMR spectroscopy and an accompanying molecular modelling, both quantitative anisotropic ring current effects of the aromatic moieties and steric substituent effects were employed to determine the stereochemistry of the naphthoxazinobenzoxazine derivatives (Scheme 34). 59

Synthesis of naphthoxazinoisoquinolines/ naphthoxazinoquinolines
In 2011, unexpected reactions between 1-a-aminobenzyl-2naphthol (1), N-benzyl-1-a-aminobenzyl-2-naphthol (113), 1aminomethyl-2-naphthol hydrochloride (114) and 6,7-dimethoxy-3,4-dihydroisoquinoline (115) to furnish naphth[1,2e][1,3]oxazino[2,3-a]isoquinolines 116 and 117 were reported.The reaction conditions involved classical heating at 80 °C in MeCN for 22 h, or the use of microwave conditions (100 °C), which allowed a reduction of the reaction time to 90 min and resulted in somewhat higher yields of the product.The proposed reaction pathway for the formation of 117 is depicted in Scheme 35.The rst step is the loss of ammonia, leading to 118.The next step involves nucleophilic attack of the dihydroisoquinoline nitrogen on the C]C bond, forming 119.The driving force for this step is aromatization.The ionic intermediate 119 is stabilized by attack of the phenolic ion on the imine carbon of the dihydroisoquinoline, leading to 117. 60 Next, Folup and co-workers described a highly functionalized aminonaphthol derivative 120 converted to the corre- derivatives 121-124 in ring-closure reactions with formaldehyde in CHCl 3 , benzaldehyde in MeOH and/or phosgene in toluene at room temperature.The products obtained via the reactions of 120 with substituted benzaldehydes can potentially furnish vecomponent tautomeric mixtures 124 in CD 2 Cl 2 at 300 K (Scheme 36). 61n 2012, the syntheses of naphth[1,2-e][1,3]oxazino[3,2-c] quinazolin-13-one derivatives 125 in 37-74% yields were reported by the solvent-free heating of benzyloxycarbonylprotected intermediates 126 with MeONa for 10-65 min.For intermediates 126, prepared by the reactions of substituted aminonaphthols 127 with benzyl N-(2-formylphenyl)carbamate in the presence of Et 3 N in EtOH for 2-4 days at room temperature, not only the expected trans ring form 128 and chain form 126, but also the rearranged chain form 129 as a new tautomer were detected in DMSO at room temperature.The quantity of 130 in the tautomeric mixture was changed with time.Moreover, conformational analyses of the target heterocycles 125 by NMR spectroscopy and accompanying theoretical calculations at the DFT level of theory revealed that the oxazine ring preferred a twisted chair conformation and the quinazolone ring was planar.Besides the conformations, both the congurations at C-7a and C-15 and the preferred rotamers of the 1-naphthyl substituent at C-15 were assigned, which allowed evaluation of the aryl substituent-dependent steric hindrance in this part of the molecules (Scheme 37). 62n 2017, Baruah and co-workers developed visible light intramolecular cross dehydrogenative coupling of 1-aminoalkyl-2-naphthols 131 to 1,3-oxazines 132 in 53-78% yields using green LED lamp as the light source and eosin Y functions as photoredox catalyst in CH 3 CN at room temperature for 10-18 h.Organic photoredox catalyst eosin Y is used which is very cheap and non-hazardous.Moreover, aerial oxygen is used as the oxidant.In the proposed mechanism, the reaction proceeds through the formation of iminium ion intermediate (Scheme 38). 63er that, the reaction of Betti base 133 in H 2 O in the presence of O 2 as the sole oxidant at 100 °C afforded 1,3-oxazine 134 in 71% yield aer 12 h.The proposed mechanism is illustrated in Scheme 39.Compound 133 gets oxidized by oxygen to iminium ion 135.They believe that a polar solvent might help eliminate the -OOH group from 136 through solvation.The iminium ion 135 then undergoes fragmentation to quinone methide 137 and 3,4-dihydroisoquinoline 138.These two fragments are then coupled with each other through [4 + 2]cycloaddition to form the product 134. 64

The other fused-heterocycles
In 2007, Zhang and co-workers prepared macrocyclic compound 139 in 87% yield by the reaction of C 2 -symmetric aminonaphthol 140 with 2,6-dichloromethylpyridine using K 2 CO 3 in dry DMF at room temperature for 36 h.Compound 139 exhibited excellent ability to discriminate the enantiomers of a broad variety of carboxylic acids by 1 H-NMR spectroscopy (Scheme 40). 65er that, a series of chiral phosphoramidite ligands 141 were prepared in high yields from unsymmetrical secondary amines 142 and chiral BINOL.Alkylation of the hydroxy group of naphthols 142 with methyl or ethyl iodide in acetone aer protection of the amino group with benzyl chloroformate 143 in dichloromethane provided 144 in quantitative total yields.Hydrogenolysis of carbamates 144 with 5% palladium on carbon in alcohol afforded free secondary amines 145 in good yields.The free amines reacted with phosphorus trichloride and chiral BINOL to provide chiral phosphoramidites 141 in 32-74% yield aer ash chromatography (Scheme 41).The ligands with (S,R,R)-conguration were effective for the palladiumcatalyzed enantioselective hydrosilylation of styrene derivatives.The resulting silanes were oxidized to provide secondary alcohols in medium to high yields (up to 96% yield) and good enantiomeric excesses (up to 97% ee). 66n addition, Hutton and co-workers constructed boronate complex 146 in 97% yield by the reaction of (S)-1 with glyoxylic acid and phenylboronic acid in DMF/1,2-dichloroethane at 50 °C for 24 h.Formation of 146 must involve three processes: complexation of aldimine 147 with phenylboronic acid would generate boronate complex 148, with subsequent tautomerization of the aldimine to the ketimine generating nal complex 146 (path A).Alternatively, tautomerization of the aldimine to the ketimine 149 could precede complexation with the boronic acid (path B) as shown in Scheme 42.To achieve enantioselective formation of boronate complex 146, the reaction must proceed by path A, with diastereoselective formation of glyoximine-boronate complex 148 controlled by the conguration at the carbon stereocenter.The alternative reaction sequence (path B), in which tautomerization of the aldimine 147 to the achiral ketimine 149 precedes complexation with boronic acid, would result in formation of complex 146 as a racemate. 67n 2009, Olyaei and his group reported synthesis of naphth [1,2-f][1,4]oxazepine-3,4-dione heterocycles 150 in 76-85% yields by the reaction of N-heteroaryl aminonaphthols 151 with oxalyl chloride in dry 1,2-dichloroethane containing pyridine under argon atmosphere.The reaction mixture was stirred for 30 min at 0-5 °C, then 30 min at room temperature, and reuxed for an additional 45 min.This method with the advantages, such as generality and simplicity of procedure, lower reaction time, elimination of acid catalyst, and obtaining excellent yields are worth noting (Scheme 43). 68 2014, the reaction of N-substituted 1-(a-aminobenzyl)-2naphthols 152 with phosphorus(III) compounds in reuxing benzene in the presence of diethylamine hydrochloride as catalyst for 5-16 h afforded cyclic phosphorylated diastereomeric derivatives 153, followed by addition of elemental sulfur under reux conditions for 2 h resulted cyclic thiophosphorylated diastereomeric derivatives 154 in 25-81% yields as depicted in Scheme 44. 69er that, Shahrisa and his group reported chemoselective sequential reactions for the synthesis of 12H-benzo 157 occurred.The two-step sequence proceeded efficiently in a one-pot manner by heating of 157 in the presence of CuI (10 mol%), picolinic acid (20 mol%) and K 3 PO 4 at 100 °C in DMSO for 18 h to afford the desired product 155 in 78-83% yields.Moreover, compounds 156 were achieved in 63-77% yields by heating of 157 in toluene at 110 °C using Cs 2 CO 3 , CuI and L-proline for 6-8 h (Scheme 45). 70ext, the reaction of (R,R)-Betti base 158 with commercially available dichloro(methoxy)phosphine in the presence of triethylamine in tetrahydrofuran (THF) at 0 °C to room temperature for 3 h led to the formation of two phosphorus-containing species phosphoramidites 159, in a ratio of (S p ) : (R p )/80 : 20.Subsequent, the mixture of P-epimers 159 was treated with a solution of BH 3 $SMe 2 at room temperature for 14 h to give the borane adducts 160$BH 3 in 84% yield.When the same reaction sequence was carried out in CH 2 Cl 2 or THF with triethylamine or n-BuLi as base, phosphoramidochloridite 161 was formed.In the following reaction with methanol the P-epimers of the resulting phosphoramidite 160 were obtained (Scheme 46). 71n 2016, the ring closure of the Betti bases 163-166 by using a 35% solution of CH 2 O as cyclizing agent in CH 2 Cl 2 at room temperature led to the formation of naphthoxazines, isoquinolinoxazines and quinolinoxazines 167-170 in 78-92% yields.The reactions proved to be complete aer relatively short reaction times (20-30 min) and the desired products 167-170 were isolate (Scheme 47). 72n 2017 Teimuri-Mofrad et al. reported synthesis of oxazepine derivatives 171 in 75-83% yields via intramolecular Ullmann reaction of Betti bases 172 in the presence of catalytic amount of CuI, L-proline and K 2 CO 3 in DMF at 110 °C for 18 h followed by subsequent oxidation reaction as shown in Scheme 48. 73urther, a series of naphth [1,3]oxazino-benzazepines 173 in 7-48% yields and -thienopyridines 174 in 10-49% yields were synthesized using a modied Mannich-type synthetic pathway by the reaction of 4,5-dihydro-3H-benz[c]azepine 175 or 6,7dihydrothieno[3,2-c]pyridine 176 and different substituted aminonaphthols 177 and 178 using microwave irradiation in 1,4-dioxane in the presence of Et 3 N at a temperature of 80 °C for 20-80 min.In these reactions, the mixture of diastereomers was formed and the conversion and the diastereomeric ratio were monitored by crude product NMR spectra in all cases (Scheme 49). 74ulop and co-workers reported synthesis of non-racemic naphth [1,3]  TBN dramatically increased the P-gp-mediated cellular uptake of the uorescent substrate rhodamine 123.Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. 83n 2011, a variety of mono-sulfonamide organocatalysts 226 prepared in 12-56% yields by coupling of (S)-1 with various sulfonyl chlorides in CH 2 Cl 2 at room temperature for 24 h and applied as catalyst to the asymmetric hetero-Diels-Alder reaction of ethyl glyoxylate with Danishefsky's diene.The sulfonamides exhibited catalytic activity as hydrogen bond donor (Scheme 59). 84n 2015, Baruah et al.The corresponding aryl methylnaphthols which contain a wide range of substituents, could be obtained in 71-89% yields.The reaction does not use any hazardous metal catalyst or reductant.The method uses p-TSA as catalyst which is a convenient, easily available and cheap reagent.Moreover, the reaction is general and having wide substrate compatibility.A mechanistic proposal involving elimination-addition mechanism is described in Scheme 60. 85 In addition, the Betti bases 230 were diazotized by treating with equivalent amounts of sulfanilamide or p-aminoacetophenone in the presence of sodium nitrite and hydrochloric acid at 0-5 °C.Aer 5-10 min, azo dye compounds 231 obtained in 54-92% yields (Scheme 61). 86n 2016, Deb and co-workers reported the reaction of Betti bases 232 with various heterocycles like indole, 5-pyrazolone, 6aminouracil, and 4-hydroxycoumarin for the formation of  room temperature under argon for 24 h.It should be noted that N-Boc-protected Betti base 237 synthesized in 80.3% yield by the reaction of (±)-and (S)-(+)-1-(a-aminobenzyl)-2-naphthol (1) with di-tert-butyl dicarbonates in CH 2 Cl 2 at room temperature for 1 h followed by reuxing for 5 h.This method is simple and effective approach to synthesis of racemic and enantiopure phosphoric acids containing chiral Betti base fragment with free amino group (Scheme 63). 88ext, an efficient route for benzoylation or formylation of naphthols for the synthesis of hydroxyaryl ketones 238 developed via oxidative deamination of Betti bases 239 in the presence of copper salt catalyst with TBHP as an oxidant in water as a reagent as well as solvent.The products were obtained in 62- Baruah and co-workers published the synthesis of compounds 242 in 58-86% yields by the reaction of Betti bases 243 with indoles using p-TsOH$H 2 O (0.1 eq.) as catalyst in toluene at 100 °C for 3-5 h.Electron-donating groups on the aryl ring of Betti bases decreased the product yield, whereas electron-withdrawing groups increased the yield.Betti bases having ortho-substituted aryl rings provided lower yields with longer reaction times.When the reaction was carried out by 2.0 equivalents of indoles in the presence of p-TsOH$H 2 O (0.25 eq.), bis(indolyl)methanes 244 were obtained in 52-65% yields aer 3-4 h.Also, the reaction of 243 with indoles using p-TsOH$H 2 O (0.1 equiv.) in toluene at 100 °C for 3-5 h and then I 2 (0.1 equiv.)and TBHP (2.0 equiv.)afforded chromeno[2,3-b]indoles 245 aer 2.5 h by stirring the mixture at room temperature.Moreover, the reactions do not use any expensive metal catalyst or solvent.Neither dry solvents nor precautions for an inert atmosphere are required (Scheme 65). 90n 2017, the reaction of racemic urea 246 with diethyl chlorophosphite in the presence of potassium t-butoxide in benzene/diethyl ether at room temperature for 4 h followed by the treatment with elemental sulfur at reux conditions for 2 h furnished bis-thiophosphorylated thiourea 247 in 51.5% yield.Then, the reaction of thiourea 246 with diethyl chlorophosphate in the presence of potassium tert-butoxide as the base in benzene/diethyl ether at room temperature for 24 h resulted thiourea 248 in 71.3% yield.Also, the reaction of 248 with an excess of bromotrimethylsilane in methylene chloride at room temperature for 24 h afforded bisilylated phosphorylthiourea methide intermediate.The addition of thiol onto the in situ generated ortho-quinone methide could result in the formation of the desired product 259.Saturated brine solution was iden-tied as a suitable medium for the synthesis of thioethers from aminophenol derivatives.Control experiments revealed that the nature of leaving group and reaction atmosphere plays a vital role in determining the yield of the products. 94ecently, synthesis of 1-[(1S)-(4-uorophenyl)-((1 0 S)-1 0naphthalen-1-yl-ethylamino)-methyl]-naphthalen-2-ol 260 in 79% yield reported by the triation reaction of (S,S)-aminobenzylnaphthol 261 with triuoromethanesulfonic anhydride in the presence of pyridine in dichloromethane at room temperature for 16 h as shown in Scheme 70.Compound 260 can be used as valuable intermediate in the future synthesis of aminophosphine, to be used in asymmetric catalysis. 95

Conclusions
The Betti reaction is a multicomponent reaction that allows for the synthesis of various compounds containing C-C and C-N bonds in a single step.The Betti bases exhibit signicant versatility as essential structural motifs in synthetic organic compounds, especially in the synthesis of heterocyclic molecules.This is attributed to their capacity for incorporating diverse functional groups, including -OH and -NH.This review explores transformations of the Betti base derivatives to the heterocyclic compounds such as naphthoxazines, bisnaphthoxazines, naphthopyrrolooxazines, naphthopyridooxazines, naphthooxazinoazepines, naphthoxazinobenzoxazines, naphthoxazinoisoquinolines, naphthoxazinoquinolines and the other fused-heterocycles.Furthermore, the review investigates the applications of these transformed compounds in relation to their pharmacological properties.We hope this review will promote the continued interest in the conversion of the Betti bases to the organic compounds and will provide a comprehensive and valuable insight to ll the gap in the reactions of Betti bases and their transformations into target compounds in the future.
The reaction of Betti base derivatives 78 with Ag 2 O in xylene at 140 °C afforded the desired product 77 in 45-95% yields.A probable mechanism is depicted in Scheme 29.First, Betti base 78 reacted with Ag 2 O to provide the corresponding o-quinone methide 79.Thus a 1,6-H (alpha to the nitrogen) transfer can be operative on 79 to furnish the zwitterionic intermediate 80.Alternatively, 80 can also be formed via mesomerization of quinone methide 79 followed by a proton transfer.Protonation of 80 and subsequent diastereoselective cyclization of the resulting iminium ion 81 gave rise to trans-oxazine 77.The electron-withdrawing group on Ar and the electron donating nature of R will stabilize the zwitterionic intermediate 80.The expected lower yields for morpholine derivatives are due to the reduced stability of the zwitterionic intermediate 80 because of the negative inductive effect of the ring oxygen atom. 54In 2016, Karade et al. synthesized a series of 1,3-napthoxazines 82 in 58-81% yields by the reactions of 1-(a-aminoalkyl)-2-naphthols 83 with (diacetoxyiodo)benzene (DIB) in CH 2 Cl 2 at room temperature for 6-24 h.This synthesis of 1,3-naphthoxazine involves transition metal-free cross-dehydrogenative C-O bond formation at sp 3 C-H bond adjacent to tertiary nitrogen.The tentative mechanism is shown in Scheme 30.The reaction of DIB with phenolic substrate 83 can inhibit the oxidative dearomatization due to the formation of putative six membered iodine(III) heterocycle 84.